Mucosal T cells in gut homeostasis and inflammation - PubMed (original) (raw)

Mucosal T cells in gut homeostasis and inflammation

Femke van Wijk et al. Expert Rev Clin Immunol. 2010 Jul.

Abstract

The antigen-rich environment of the gut interacts with a highly integrated and specialized mucosal immune system that has the challenging task of preventing invasion and the systemic spread of microbes, while avoiding excessive or unnecessary immune responses to innocuous antigens. Disruption of the mucosal barrier and/or defects in gut immune regulatory networks may lead to chronic intestinal inflammation as seen in inflammatory bowel disease. The T-cell populations of the intestine play a critical role in controlling intestinal homeostasis, and their unique phenotypes and diversities reflect the sophisticated mechanisms that have evolved to maintain the delicate balance between immune activation and tolerance at mucosal sites. In this article, we will discuss the specialized properties of mucosal T cells in the context of immune homeostasis and inflammation.

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Figures

Figure 1

Figure 1. Intestinal T-cell subsets

The lamina propria and epithelium of the intestine harbor diverse populations of T cells. Conventional or ‘type a’ mucosal T cells that have matured in the thymus along the conventional selection pathway migrate, after antigen priming in the mesenteric lymph nodes, mainly to the lamina propria but also the epithelium. Upon entry into the epithelium, these cells often coexpress the CD8αα homodimer. Most intraepithelial lymphocytes (IELs), however, belong to two subsets of unconventional or ‘type b’ mucosal T-cell populations: the TCRγδ+ CD8αα+ IELs that are thymus derived and develop along the double-negative pathway and the TCRαβ+ CD8αα+ IELs that have matured and differentiated in the thymus along the agonist-selection pathway. Both subsets migrate as antigen-experienced directly to the intestine where the majority of cells upregulate CD8αα, while some remain double negative. DN: Double negative; TCR: T-cell receptor.

Figure 2

Figure 2. Mucosal T-cell regulation and activation

The functionally diverse T-cell populations of the intestine that are shaped by the gut environment are important players in sustaining the delicate immune balance between activation and regulation. The CD8αα+ IELs of the intestine play a crucial role in protecting the mucosal barrier. They are involved in maintaining and restoring barrier homeostasis by stimulating IEC turnover. Upon pathogen entry, rapid activation and high cytolytic activity of the CD8αβ+ IELs contribute to the prevention of pathogen spreading by killing infected IECs. The activation of IELs is highly controlled through the expression of inhibitory receptors that may alter the threshold for activation. In some conditions, such as celiac disease, activation of CD8αβ+ cytotoxic T lymphocytes is associated with epithelial damage. In the lamina propria (LP), all classical CD4+ Th subtypes are present. Under the influence of IECs and IELs, LP DCs acquire the ability to produce RA, thereby inducing gut-homing receptors during CD4 T-cell priming in the mLNs. The LP of the gut is enriched with both Foxp3+ Tregs and Th17 cells. Gut-derived CD103+ DCs favor the conversion of Foxp3+ iTregs in a RA- and TGF-β-mediated fashion, whereas activated DCs promote the differentiation of IL-17-producing Th17 cells via a combination of IL-6 and TGF-β. This pro- and anti-inflammatory immune deviation of iTreg and Th17 is reciprocally controlled by RA and IL-6. Specific bacteria in the small intestine have been shown to be crucial for Th17 induction, possibly through the induction of ATP release by DC. Finally, the LP is also home to agonist-selected Foxp3-expressing nTregs that, like iTregs, can produce the suppressive cytokines IL-10 and TGF-β. T helper subsets can also contribute to immune pathogenesis and damage under inflammatory conditions. Th1 and Th17 cells are implicated in Crohn’s disease, Th1 cells in celiac disease and Th2 cells in ulcerative colitis. Under these proinflammatory conditions, cytokines secreted by IECs and DCs such as IL-12, IL-23, TSLP and IL-25 promote differentiation of inflammatory Th1, Th17 and Th2 subsets, respectively. DC: Dendritic cell; IEC: Intestinal epithelial cell; IEL: Intraepithelial lymphocyte; iTreg: Induced regulatory T cell; mLN: Mesenteric lymph node; nTreg: Naturally occurring regulatory T cell; RA: Retinoic acid; TSLP: Thymic stromal lymphopoietin.

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References

    1. Hayday A, Theodoridis E, Ramsburg E, Shires J. Intraepithelial lymphocytes: exploring the Third Way in immunology. Nat. Immunol. 2001;2(11):997–1003. - PubMed
    1. Campbell DJ, Butcher EC. Rapid acquisition of tissue-specific homing phenotypes by CD4+ T cells activated in cutaneous or mucosal lymphoid tissues. J. Exp. Med. 2002;195(1):135–141. - PMC - PubMed
    1. Iwata M, Hirakiyama A, Eshima Y, et al. Retinoic acid imprints gut-homing specificity on T cells. Immunity. 2004;21(4):527–538. - PubMed
    1. Probert CS, Saubermann LJ, Balk S, Blumberg RS. Repertoire of the αβ T-cell receptor in the intestine. Immunol. Rev. 2007;215:215–225. - PubMed
    1. Cheroutre H, Madakamutil L. Mucosal effector memory T cells: the other side of the coin. Cell. Mol. Life Sci. 2005;62(23):2853–2866. - PMC - PubMed

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